Microperfusive Electrical Stimulation

ABSTRACT

A method of treating a patient in cardiac arrest (e.g., in fibrillation, electrochemical dissociation, or asystole), the method comprising delivering an agent for enhancement of cardiac function to the coronary arteries of the patient; and microperfusing the patient&#39;s cardiac tissue by electromagnetically stimulating the cardiac issue at an energy level below a threshold sufficient to defibrillate the heart.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of and claims priority toU.S. application Ser. No. 10/868,395, filed on Jun. 15, 2004, whichapplication claims priority to U.S. Provisional Application Ser. No.60/564,160, filed on Apr. 20, 2004. Both applications are herebyincorporated by reference.

TECHNICAL FIELD

This invention relates to the treatment of cardiac arrest, and inparticular to the electromagnetic stimulation of the heart for thetreatment of cardiac arrest.

BACKGROUND

Cardiac Arrest, or Sudden Death, is a descriptor for a diversecollection of physiological abnormalities with a common cardiacetiology, wherein the patient typically presents with the symptoms ofpulselessness, apnea and unconsciousness. Cardiac arrest is widespread,with an estimated 300,000 victims annually in the U.S. alone and asimilar estimate of additional victims worldwide. Early defibrillationis the major factor in sudden cardiac arrest survival. There are, infact, very few cases of cardiac arrest victims saved which were nottreated with defibrillation. There are many different classes ofabnormal electrocardiographic (ECG) rhythms, some of which are treatablewith defibrillation and some of which are not. The standard terminologyfor this is “shockable” and “non-shockable” ECG rhythms, respectively.Non-shockable ECG rhythms are further classified into hemodynamicallystable and hemodynamically unstable rhythms. Hemodynamically unstablerhythms are those which are incapable of supporting a patient's survivalwith adequate blood flow (non-viable). For example, a normal sinusrhythm is considered non-shockable and is hemodynamically stable(viable). Some common ECG rhythms encountered during cardiac arrest thatare both non-shockable and hemodynamically unstable are: bradycardia,idioventricular rhythms, pulseless electrical activity (PEA) andasystole. Bradycardias, during which the heart beats too slowly, arenon-shockable and also possibly non-viable. If the patient isunconscious during bradycardia, it can be helpful to perform chestcompressions until pacing becomes available. Idioventricular rhythms, inwhich the electrical activity that initiates myocardial contractionoccurs in the ventricles but not the atria, can also be non-shockableand non-viable (usually, electrical patterns begin in the atria).Idioventricular rhythms typically result in slow heart rhythms of 30 or40 beats per minute, often causing the patient to lose consciousness.The slow heart rhythm occurs because the ventricles ordinarily respondto the activity of the atria, but when the atria stop their electricalactivity, a slower, backup rhythm occurs in the ventricles. PulselessElectrical Activity (PEA), the result of electro-mechanical dissociation(EMD), in which there is the presence of rhythmic electrical activity inthe heart but the absence of myocardial contractility, is non-shockableand non-viable and would require chest compressions as a first response.Asystole, in which there is neither electrical nor mechanical activityin the heart, cannot be successfully treated with defibrillation, as isalso the case for the other non-shockable, non-viable rhythms. Pacing isrecommended for asystole, and there are other treatment modalities thatan advanced life support team can perform to assist such patients, e.g.intubation and drugs. The primary examples of shockable rhythms that canbe successfully treated with defibrillation are ventricularfibrillation, ventricular tachycardia, and ventricular flutter.

Normally, electrochemical activity within a human heart causes theorgan's muscle fibers to contract and relax in a synchronized manner.This synchronized action of the heart's musculature results in theeffective pumping of blood from the ventricles to the body's vitalorgans. In the case of ventricular fibrillation (VF), however, abnormalelectrical activity within the heart causes the individual muscle fibersto contract in an unsynchronized and chaotic way. As a result of thisloss of synchronization, the heart loses its ability to effectively pumpblood. Defibrillators produce a large current pulse that disrupts thechaotic electrical activity of the heart associated with ventricularfibrillation and provides the heart's electrochemical system with theopportunity to re-synchronize itself Once organized electrical activityis restored, synchronized muscle contractions usually follow, leading tothe restoration of effective cardiac pumping.

First described in humans in 1956, transthoracic defibrillation hasbecome the primary therapy for cardiac arrest, ventricular tachycardia(VT), and atrial fibrillation (AF). Monophasic waveforms dominated until1996, when the first biphasic waveform became available for clinicaluse. Attempts have also been made to use multiple electrode systems toimprove defibrillation efficacy. While biphasic waveforms andmultiple-electrode systems have shown improved efficacy relative tomonophasic defibrillation, there is still significant room forimprovement: shock success rate for ventricular fibrillation (VF)remains less than 70% even with the most recent biphasic technology. Inthese cases, shock success was defined to be conversion of a shockablerhythm into a non-shockable rhythm, including those non-shockablerhythms which are also non-viable. Actual survival-to-hospital-dischargerates remain an abysmal ten percent or less. Survival rates from cardiacarrest remain as low as 1-3% in major U.S. cities, including those withextensive, advanced prehospital medical care infrastructures.

The initial rhythm following a defibrillation shock is rarely aperfusing, viable rhythm and almost always is asystole or PEA, neitherof which is treatable with defibrillation. In addition, recent studieshave shown rates of ventricular fibrillation (VF) and shockableventricular tachycardias (VT) to be unexpectedly low. A recent reportfrom Goteborg, Sweden shows VF to be present in only 39% of cases.Similar results have been reported from Seattle and Ontario, Canada.Ornato et al in a study of hospital cardiac arrest found only 25% ofpatients presented with a shockable rhythm (VF/VT); 66% presented withnon-shockable rhythms asystole and PEA. There is even retrospectiveclinical data that indicates that the rates of non-shockable PEA andasystole are increasing in cardiac arrest victims.

Given that neither of these rhythms is treatable with defibrillation,there is a justifiable clinical concern that the treatment protocolscurrently recommended by expert groups such as the American HeartAssociation are inadequate. A recent publication by Ewy proposed thatcertain elements of the present AHA guidelines [AHA Guidelines 2000 forCPR and Emergency Cardiovascular Care, Circulation 2000; 102(8),Supplement] regarding Basic and Advanced Life Support (BLS, ALS) fieldprotocols may be contributing factors in the poor survival rates forcardiac arrest. The term basic life support (BLS) refers to maintainingairway patency and supporting breathing and circulation without the useof equipment other than a protective shield. BLS comprises the elements:initial assessment; airway maintenance; expired air ventilation (rescuebreathing); and chest compression. When all three (airway breathing,circulation) are combined the term cardiopulmonary resuscitation (CPR)is used. Personnel trained in ALS will also deliver drugs, as well assuch advanced techniques as intubation, administration of intravenousfluids and suturing in addition to BLS techniques. In the currentlyrecommended treatment protocols, BLS personnel should perform CPR oncardiac arrest victims whose rhythm is either PEA or asystole; ALSpersonnel have the additional treatments available of intubation,intravenous administration and the drugs epinephrine and atropine. Noneof these ALS techniques, however, have been particularly effective inthe treatment of either PEA or asystole. Assuming a rate of PEA andasystole of 66% in cardiac arrest victims, 400,000 of the 600,000 totalworldwide cardiac arrest victims would present in physiological statesfor which there was no effective treatment for their condition, whichhas a 0% survival rate, it should be noted, if left untreated.

A new protocol, coined “CPR First”, is being considered whichreemphasizes the importance of perfusion. It is currently proposed asfollows: for patients with a known (witnessed) collapse time of lessthan 4 minutes, perform the present field protocol; for patients withprolonged (greater than 4 minutes) or unknown collapse time, (1)immediately begin uninterrupted chest compressions prior to adefibrillation shock (various lengths of time for compression are beingconsidered, starting with 90 seconds or greater), (2) only apply onedefibrillation shock (e.g., a biphasic waveform) at the end of the firstchest compression cycle, and (3) followed immediately by 200uninterrupted chest compressions prior to a cardiac rhythm analysis byan automated external defibrillator (AED) or by the rescuer trained inthe analysis of ECG rhythms, providing a defibrillation shock asnecessary (repeat steps 1-3 for as long as deemed necessary). As long asthe patient remains unconscious, the rescuer can alternate between useof the defibrillator (for analyzing the electrical rhythm and possiblyapplying a shock) and performing cardiopulmonary resuscitation (CPR).CPR generally involves a repeating pattern of five or fifteen chestcompressions followed by providing the victim with a number of breaths.CPR is generally ineffective against abnormal rhythms, but it does keepssome level of oxygenated blood flow going to the patient's vital organsuntil an advanced life support team arrives.

The treatment window for cardiac arrest is very narrow. Long termsurvival rates from the time of victim collapse decrease at a roughlyexponential rate with a time constant of roughly 2 minutes. Thus, justtwo minutes of delay in treatment using the currently recommendedtreatment protocols result in a long term survival rate of 30-35%. After15 minutes, the long term survival rates are below 5%. While theresponse times of emergency medical systems have improved significantlyover the last quarter century to the point that average times fromemergency call to arrival at the victim is typically 9 minutes or less,bystander delays in making the emergency call typically add 2-3 minutesto the total arrest time, for a total of 11-12 minutes. In addition, thebystander making the emergency call may not even have witnessed thecardiac arrest, which may have occurred at some point in the past.Unwitnessed arrest accounts for at least half of all cardiac arrests.Cardiac arrest downtimes are only reported for witnessed arrests; it hasbeen estimated, however, that if unwitnessed arrests were to beincluded, the average downtime for all victims would exceed 15 minutes.At the time of initial collapse, the ECGs of nearly all cardiac arrestvictims are shockable rhythms such as VF or VT; after 15 minutes,however, the ECG rhythms of most cardiac arrest victims have degeneratedinto the non-shockable rhythms of PEA or asystole.

Excitation-Contraction (E-C) coupling describes the process by which theelectrical signal, initiated in the S-A node in normal hearts, isconverted to a mechanical contraction in the myocardial cells.Excitation-contraction coupling begins when an action potentialdepolarizes the plasma membrane surrounding the myocardial cell, whichgenerates an electrical signal by allowing ions to flow throughion-selective channels in the plasma membrane. Two cations, sodium andcalcium, carry the inward currents that depolarize the heart, while thecation potassium carries the outward current that repolarizes the heartand is the primary determinant of the heart's resting potential.Excitation of the cells of the atria and ventricles begins when openingof the sodium channels generates an inward (depolarizing) sodiumcurrent. The resulting change in membrane potential opens calciumchannels that trigger calcium release from the sarcoplasmic reticulum.

Calcium ions, by carrying signals generated at the cell surface to avariety of intracellular proteins and organelles, can be viewed as themost important of the intracellular messengers. Myocardial cells usecalcium as the essential final step in excitation-contraction coupling,the process by which depolarization at the cell surface initiates theinteractions between the contractile proteins that cause the walls ofthe heart to develop tension and contract.

Calcium binding to troponin-C triggers interactions between actin andmyosin by reversing an inhibitory effect of the regulatory proteins.This response begins with a series of cooperative interactions betweencalcium-bound troponin-C and other proteins of the thin filaments:actin, tropomyosin, troponin-I, and troponin-T. Calcium binding totroponin-C weakens the bond linking troponin-I to actin, causing astructural rearrangement of the regulatory proteins that shifts thetropomyosin deeper into the grooves between the strands of actin. Thisrearrangement exposes active sites on actin for interaction with themyosin cross bridges.

The ultrastructure of the myocardial cell is shown in FIG. 1. Thesarcomere is the functional unit of the contractile apparatus. Thesarcomere is defined as the region between the successive Z-lines andcontains two half-I-bands and one A-band. Contractile proteins arearranged in a regular array of thick and thin filaments (seen in crosssection at the left). The A-band represents the region of the sarcomereoccupied by the thick filaments into which the thin filaments extendfrom either side. The I-band is the region of the sarcomere occupiedonly by the thin filaments; these extend toward the center of thesarcomere from the Z-lines, which bisect each I-band. The sacroplasmicreticulum, a membrane network that surrounds the contractile proteins,consists of the sarcotubular network at the center of the sarcomere andthe cisternae, which abut the t-tubules and the sarcolemma, so that thelumen of the t-tubules carries the extracellular space toward the centerof the myocardial cell.

At rest, active transport processes (mainly the sodium-potassium pump)maintain electrochemical gradients across the sarcolemmal membrane.Consequently, a resting membrane potential is established with the cellinterior being negative relative to the extracellular space.Depolarization of the cardiac sarcolemmal membrane occurs largely due toopening of sodium channels, which results in an influx of sodium and arapid rise in membrane potential from negative to positive values. Thischange in membrane potential is ultimately translated into an increasein intracellular cytosolic calcium, binding of calcium to thecontractile protein complex in the myofibrils, and cell shortening(contraction). Relaxation occurs as the resting sarcolemmal membranepotential is reestablished, intracellular cytosolic calcium decreases,and calcium dissociates from the contractile protein complex.

FIG. 2, shows the primary calcium fluxes of both the E-C coupling andrelaxation. The thickness of each arrow represents the magnitude of thecalcium flux, and their vertical orientation describe whether or not theflux is generated by passive or active transport: downwardly-directedarrows represent passive flux while upwardly-directed arrows representenergy-dependent active calcium transport. Most of the calcium thatenters the cell from the extracellular fluid via the L-type calciumchannels (arrow A) triggers calcium release from the sacroplasmicreticulum; only a small portion directly activates the contractileproteins (arrow Al). Calcium is actively transported back into theextracellular fluid by the plasma membrane calcium pump ATPase (arrowB1) and the Na/Ca exchanger (arrow B2). The sodium that enters the cellin exchange for calcium (dashed line) is pumped out of the cytosol bythe sodium pump. The channels providing inward-directed calcium fluxare: 1) L-type channels, located in the transverse tubular system, inclose proximity to the calcium release channels of the sarcoplasmicreticulum; and 2) T-type channels not concentrated in t-tubules but canbe found on the plasma membrane of the myocardial cells. The channelsproviding outward-directed calcium flux are: 1) plasma membrane calciumpump (PMCA), a low volume pump; and 2) the Na/Ca exchanger.

Calcium entry via L-type calcium channels is among the most importantdeterminants of myocardial contractility. This calcium entry serves twofunctions: it triggers the opening of the intracellular calcium releasechannels in the sarcoplasmic reticulum and provides most of theactivator calcium that binds to troponin, and it fills the internalcalcium stores. Only a small amount binds directly to the contractileproteins of the adult heart, which depends mainly on the intracellularcalcium cycle. B-adrenergic agonists are known to increase L-typechannel flow, while both calcium and beta-channel blockers are known toinhibit calcium flux through the L-type calcium channels.

The Na/Ca exchanger transports three sodium ions in one direction acrossthe membrane for a single calcium ion that moves in the oppositedirection, which means that the Na/Ca exchange is electrogenic.Therefore, calcium efflux, which relaxes the heart, is favored duringdiastole, whereas calcium influx increases contractility during systole.

Two calcium fluxes are regulated by the sacroplasmic reticulum: calciumefflux from the sarcolemmal cisternae via calcium release channels(arrow C) and calcium uptake into the sarcotubular network by thesarco(endo)plasmic reticulum calcium pump ATPase (arrow D). Calciumdiffuses within the sacroplasmic reticulum from the sarcotubular networkto the sarcolemmal cisternae (arrow G), where it is stored in a complexwith calsequestrin and other calcium-binding proteins. Calcium bindingto (arrow E) and dissociation from (arrow F) high-affinity calciumbinding sites of troponin-C activate and inhibit the interactions of thecontractile proteins. Calcium movements in and out of the mitochondria(arrow H) buffer cytosolic calcium concentration. The extracellularcalcium cycle consists of arrows A, B1, and B2, whereas theintracellular cycle involves arrows C, D, E, F, and G.

In addition, the relaxation cycle of diastole is regulated primarily bycalcium uptake by the sarco(endo)plasmic reticulum calcium(SERCA) pump(arrow D) and calcium uptake by the mitochondria (arrow H), whichtogether provide the function of normalizing and stabilizing cytosoliccalcium levels.

The most distinctive phase of the cardiac action potential is theplateau phase, generally termed phase 2 (phase 0 is the action potentialupstroke, phase 1 is the early depolarization, phase 3 is therepolarization phase, and phase 4 is diastole) generated bycounterbalancing ionic fluxes of an inward cardiac current and outwardpotassium current. The major role of the plateau is to prevent the heartfrom being reactivated before the ventricles have had time to fill afterthe preceding systole. It is calcium flux generated by L-type channelsthat provides the important duration extension of phase 2.

It is well known to those skilled in the art that the sustained energydemands of the heart can be met only by the mechanism of oxidativephosphorylation, which requires that the coronary circulation deliver anuninterrupted supply of the metabolic substrates, notably oxygen. Themyocardial ischemia induced by cardiac arrest has a number of importantmetabolic effects. In addition to the prevention of the delivery ofoxygen to the myocardial cells, there is an accumulation of protons (H+)and lactate. The resulting acidosis inhibits glycolysis and adverselyaffects contractility. Further, phosphate and potassium accumulate whichcontribute to arrhythmogenesis and reduced contractility. Cytosoliccalcium concentrations increase during ischemia due to the reducedcytosolic calcium uptake into the sarcotubular network by the SERCApump, caused by lowered ATP levels within the ischemic milieu. Duringthe early stages of ischemia, approximately <20 minutes, the Na/Caexchanger gradually drains the calcium from the cytosol. While cytosolicconcentrations of calcium may be higher due to the reduced function onthe SERCA pump, there is a net depletion of calcium within the cellduring ischemia that needs to be ameliorated before heart function canbe returned to normal. EC coupling fails under this condition resultingin PEA and asystole. Global myocardial ischemia induced during cardiacarrest has effects related to lack of oxygen, but also effects from theprevention of the removal of metabolites which accumulate in theischemic heart such as protons (H+), phosphate, potassium and lactate.Acidosis from H+ and lactate inhibits glycolosis and reduces bothcontractility and relaxation. Potassium contributes to the genesis ofarrhythmias while phosphate decreases contractility.

Prior art in defibrillation has focused on the cessation of fibrillationsuch as U.S. Pat. Nos. 3,460,542, 3,547,108, 3,716,059, 4,088,138 and4,928,690. Transcutaneous pacing of the heart for treatment ofbradycardias as well as asystole and electromechanical dissociation canbe found in such prior art as U.S. Pat. No. 4,349,030. U.S. Pat. No.5,584,866 teaches a method for achieving cardiac output duringfibrillation by increasing the amplitude of the pacing stimulus. U.S.Pat. Nos. 5.205,284, 6,253,108 B1, 6,259,949 B1, and 6,263,241 B1describe the use of higher frequency pulses in the treatment of EMD.U.S. Pat. Nos. 5,314,448 and 6,556,865 B2 both describe the electricalpretreatment of the fibrillating heart in order to improvedefibrillation results.

SUMMARY

In a first aspect, the invention features a method of treating a patientin cardiac arrest (e.g., in fibrillation, electrochemical dissociation,or asystole), the method comprising delivering an agent for enhancementof cardiac function to the coronary arteries of the patient; andmicroperfusing the patient's cardiac tissue by electromagneticallystimulating the cardiac tissue at an energy level below a thresholdsufficient to defibrillate the heart.

In preferred implementations, one or more of the following features maybe incorporated. The method of delivering the agent may compriseintravenous infusion of the agent and a circulatory enhancement methodfor delivery of the agent to the coronary arteries. The circulatoryenhancement method may comprise manual chest compressions. Thecirculatory enhancement method may comprise assistance by a chestcompression device. The circulatory enhancement method may compriseassistance by a cardiac mechanical pump. The method of delivery maycomprise direct injection into the coronary arteries. The agent maycomprise a metabolite. The metabolite may comprise at least one of, or acombination of more than one of, aspartate, glucose, NAD+, proglycogen,or 2-oxoglutarate. The agent may comprise a metabolic enhancing agent.The metabolic enhancing agent may comprise at least one of, or acombination of more than one of, epinephrine, insulin, Dobutamine,norepinephrine, catecholamine, or sympathomimetic agent. Theelectromagnetic stimulation may comprise an internally applieddefibrillation pulse. The electromagnetic stimulation may comprise anexternally applied defibrillation pulse. The invention may furthercomprise delivering a defibrillation pulse to the patient's cardiactissue following the delivering and microperfusing steps. The order inwhich the steps are performed may be delivering the agent, followed bycirculatory enhancement of the agent, followed by microperfusing. Themetabolic enhancing agent may comprise the oxidized form of nicotinamideadenine dinucleotide (NAD+). The invention may further comprisedelivering calcium. The agent may comprise at least one of the followingmetabolites: aspartate, glucose, proglycogen, or pyruvate. Thedelivering step may comprise intravenous delivery. The delivering stepmay comprise intraosseus delivery. The delivering step may comprisetranscutaneous delivery. The invention may further comprise making adetermination of whether or not the patient has suffered an asphyxialarrest or an arrest of cardiac origin. If the arrest is determined to beof cardiac origin, cardiac compressions may be performed with largercompression than would be performed if the arrest were not of cardiacorigin, and the method may further comprise ventilation. The deliveringstep may comprise cardiac compression performed by chest compression.The chest compression may comprise using equipment that automaticallyprovides chest compressions. Equipment performing chest compressions maybe electrically connected to equipment that provides the electromagneticstimulation. The equipment that provides electromagnetic stimulation maycomprise an external defibrillator and/or pacemaker. The electricalcurrent may comprise a biphasic pulse. The electrical current maycomprise a multiphasic pulse. The biphasic pulse may be about 25 to 500volts in amplitude. The invention may further comprise additionalbiphasic pulses concatenated into a multiphasic pulse train up to about1 ms to 100 ms in duration. The biphasic pulse may be about 100 to 200volts in amplitude. The biphasic pulses may comprise a series of four 10ms biphasic pulses over a duration of 40 ms. The individual biphasicpulses may be about 500 microseconds (minimum 50, maximum 1000) induration, with about a 400 microsecond first phase and about a 100microsecond second phase with a spacing between pulses of about 9.5 ms.The average amplitude of the pulse train may be adjusted by changing theduty cycle of the biphasic pulses, consistent with observation that forshorter duration biphasic pulses, less than approximately 1 ms induration, the myocardium responds to the average current of the pulsetrain.

In a second aspect, the invention features a method of stimulatingcardiac tissue, the method comprising delivering at least two distinctwaveform morphologies to the patient, either interleaved orsequentially, wherein a first waveform is configured to increase thetherapeutic effect of a first therapeutic agent on a particular cardiactissue to which the first agent is directed, and wherein a secondwaveform is configured to increase the therapeutic effect of a secondtherapeutic agent on a particular cardiac tissue to which the secondagent is directed.

In preferred implementations, one or more of the following features maybe incorporated. The first waveform may comprise a series of highfrequency pulses (e.g., 50 to 1000 microseconds in duration) and thefirst therapeutic agent may comprise a metabolic agent (e.g., glucose).The second waveform may comprise a series of low frequency pulses (e.g.,1 to 100 ms in duration) and the second therapeutic agent may compriseions such as calcium. The two waveforms may comprise a high frequency(e.g., 50 to 1000 microsecond duration) and a pacing pulse. The twowaveforms may comprise a high frequency pulse and a biphasic currentpulse. The two waveforms may be overlapping. The two pulses may besequential.

In a third aspect, the invention features a method of treating a patientin cardiac arrest (e.g., in fibrillation, electrochemical dissociationor asystole), the method comprising microperfusing the patient's cardiactissue by electromagnetically stimulating the cardiac tissue at anenergy level below a threshold sufficient to defibrillate the heart, anddelivering a pacing pulse and/or a defibrillation pulse to the patient,wherein the microperfusing, pacing, and defibrillation are delivered byvarying the duty cycle, shape, and/or rate of delivery of a series ofpulses delivered from the energy storage device.

In a fourth aspect, the invention features a method of treating apatient in cardiac arrest (e.g., in fibrillation, electrochemicaldissociation, or asystole), the method comprising delivering a pacingpulse to the cardiac tissue; and delivering a defibrillation pulse tothe cardiac tissue, wherein the pacing pulse has the same waveform asthe defibrillation pulse but with a difference in amplitude.

In a fifth aspect, the invention features a method of treating a patientin cardiac arrest (e.g., in fibrillation, electrochemical dissociation,or asystole), the method comprising delivering at least one of, or acombination of more than one of, aspartate, oxaloacetate, glutamate, or2-oxoglutarate to the patient; electromagnetically stimulating thecardiac tissue.

In preferred implementations, one or more of the following features maybe incorporated. The stimulation may comprise defibrillationstimulation. The stimulation may comprise pacing stimulation. Thestimulation may comprise below threshold defibrillation or pacingstimualation. The stimulation may comprise MPES stimulation.

Among the many advantages of the invention (some of which may beachieved only in some of its various aspects and implementations) arethat the invention can provide improved efficacies relative to priorart. None of the prior art anticipates the enhancement of circulation atthe myocardial cellular level by electromagnetic stimulation asdescribed herein, nor the use of the electromagnetic stimulation todeliver therapeutic agents into the myocardial cytosolic volume.

While survival rates for ventricular fibrillation can be as high as 50%in some emergency medical systems, survival for victims presenting inPEA or asystole is dismal, usually less than 5%. Current estimates ofprevalence of PEA and asystole as the presenting rhythm in cardiacarrest is 50%, or 200,000 victims annually worldwide who could be helpedwith a more effective treatment. Current treatment methods such as thedrug atropine or pacing have been shown to have little if any benefit tothis class of patients. Neither therapy effectively promotesself-sustaining, organized rhythmicity or contractility of the heart.CPR and chest compressions alone are helpful only for those patientswhose myocardial E-C coupling is still viable—a small subset of patientspresenting with this condition.

Electrical stimulation of ion and metabolite transfer mechanisms havethe additional benefit of a significantly shorter half life than cardiacdrugs such as beta or calcium channel blockers or vasopressin. One ofthe limitations of the use of drugs during a cardiac arrest is that thedrugs may be beneficial in achieving resuscitation, but deleterious withthe return of spontaneous circulation, e.g. a cardioactive drugs likevasopressin.

Other features and advantages of the invention will be apparent from thedrawings, detailed description, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the ultrastructure of the myocardial cell.

FIG. 2 shows the primary calcium fluxes during systole and diastole.

FIG. 3 a, 3 b are diagrammatic illustrations showing the chemomechanicalpumping sequence.

FIG. 4 a, 4 b are plots of waveforms produced by the implementation ofFIG. 5.

FIG. 5 is a schematic of the circuitry for a biphasic defibrillatorimplementation.

FIG. 6 is a block diagram of an implementation including the circuitryof FIG. 5 combined with apparatus for performing chest compression.

FIG. 7 shows an individual biphasic waveform from FIGS. 4 a, 4 b.

DETAILED DESCRIPTION

There are a great many possible implementations of the invention, toomany to describe herein. Some possible implementations that arepresently preferred are described below. It cannot be emphasized toostrongly, however, that these are descriptions of implementations of theinvention, and not descriptions of the invention, which is not limitedto the detailed implementations described in this section but isdescribed in broader terms in the claims.

It has been discovered by the inventor that, contrary to what has beenpreviously thought, the primary purpose for the transverse tubule(t-tubule) system is not for the transmission of the electricalexcitation signal deep into the cell interior, nor is the ion transportin the myocardial T-tubule system accomplished by diffusion. Rather, theprimary purpose for the t-tubule system is for ion transport to the cellinterior, and the mechanism for that transport is in actuality achemomechanical pump. It is well known to those skilled in the art thatthe t-tubule system and the sarcoplasmic reticulum do not develop inmammals until several months after birth. The number of myocardial cellsdoes not increase in mammals subsequent to birth; rather, heart size isincreased by enlargement of the individual myocardial cells. Duringdevelopment of newborn cardiac tissue, as the diameter of the cellsincrease, transcriptional triggers occur which result in t-tubulesforming primarily along the Z-lines of cells, L-type calcium channelsforming alongside the t-tubules and the sacroplasmic reticulum formingwith cisternae adjacent to the t-tubules. The reason for this structuralchange is because the increasing radii of the myocardial cells and theresulting increase in cell surface area to volume ratio makediffusion-only transport of calcium ions to the cell interiorineffective. Effective cell depolarization can be accomplished by iontransport localized to the sarcolemma, the outer surface of themyocardial cell; such is not the case for activation of the E-C couplingby calcium which requires transport of the calcium to the specificactin-myosin interface undergoing contraction.

FIGS. 3 a and 3 b depict the chemomechanical pumping sequence. Thet-tubules 100, L-type calcium channels 101, the sarcomere 102 andsacroplasmic reticulum 103 together form a chemomechanical pump systemwherein calcium-rich extracellular fluid is pumped into the t-tubulesduring relaxation and calcium-depleted fluid is pumped out the t-tubulesduring myocardial contraction. In FIG. 3 b, the myocardium is contractedand the sarcomere length, L_(Ssys) 107, is shorter than that duringmyocardial relaxation phase, L_(Sdias) 106 as shown in FIG. 3 a. Thereduced sarcomeric length results in an increased cytosolic pressure,forcing compression of the t-tubules 100 located primarily along theZ-line 104, thus reducing t-tubule diameter and causing the ejection ofthe ion and metabolite-depleted contents of the t-tubule 100 into theextracellular space 105. During diastole, sarcomere length increases,reducing cytosolic pressure, thus increasing t-tubule diameter andcausing the injection of the ion and metabolite-rich extrasystolic fluidinto the t-tubule. While other channels are located inside the t-tubulesuch as GLUT4 channels for glucose transmission across the membrane, theprimary purpose of the t-tubule is to deliver calcium to the interior ofthe myocardial cell via the L-type calcium channel 101. L-type channels101 are voltage-gated by sarcolemmal membrane potential derived fromflow of sodium and potassium ions during systole and deliver the calciumat a lower, steadier and more long-lasting rate than other ion channels.L-type calcium current is not used for contraction via activation of theactin-myosin complex. Rather, it activates the calcium induced calciumrelease (CICR) via the ryanodine receptor (RyR). CICR occurs only fromthe sarcolemmal cisternae located at the t-tubules. There is thus asignificant calcium concentration gradient along the axis of thesarcomere, with the highest concentrations located between the t-tubuleand the sarcolemmal cisternae. Calcium travels in the cytosol along thesarcomere, diffusion-driven by the concentration gradient, causingactivation of the actin-myosin complex of the sarcomere first in thoseareas along the Z-line 104 and then progressively toward those locationsfurthest away from the t-tubule 100 and Z-line 104. This results in aconcentrated contraction beginning first around the t-tubules 100,enhancing the ejection of the t-tubule contents. L-type calcium currentscontinue during much of the contraction, reducing the calcium ion andmetabolite concentration in the t-tubule fluid. During diastole,sarcomere length increases, injecting metabolite and calcium-richextracellular fluid back into the t-tubule, beginning the cycle onceagain.

In addition to the transfer of calcium and, to a lesser extent, glucoseacross the t-tubule membrane, there are the better known channelslocated on the exterior sarcolemmal membrane that transfer the variousions, nutrients and metabolites. This whole system we termmicroperfusion to differentiate it from the vascular-based circulationcarried by the coronary arteries and their branches which we termmacroperfusion.

In some implementations, interventions to enhance both macroperfusionand microperfusion either simultaneously or in specific sequences basedon the underlying clinical etiology are combined to provide the optimaltherapy for the patient.

Some implementations may be used for treating all patients in cardiacarrest of non-traumatic, non-overdose origin. Step one of the treatmentprocedure is to identify all patients whose cardiac arrest is the resultof trauma or overdose. This is easily accomplished by standard clinicalmethods, after which the patient is treated for the underlying trauma oroverdose. Patients are further categorized into those whose cardiacarrest is of cardiac etiology and those for whom the cardiac arrest wasthe result of asphyxia such as choking, hanging, drowning, etc.

The course of treatment will vary based on the etiology. In someimplementations, all treatment courses contain the following threephases: macroperfusion therapy (MPT), microperfusive electricalstimulation (MPES) and circulatory/electrical therapy (CET). MPTgenerally involves intravenous delivery of therapeutic agents, e.g. acatecholamine such as epinephrine or norepinephrine, a metabolite suchas glucose, glycogen, proglycogen or pyruvate, and a constituent ionsolution such as potassium (K⁺) or calcium (Ca⁺), followed by a periodof cardiopulmonary resuscitation (CPR). MPES involves electricalstimulation of the myocardium with the appropriate waveform morphology,frequency components and amplitude such that the various therapeuticagents are delivered to the myocardial sarcolemmal membrane and into thecytosolic space of the myocardial cells either by such mechanisms as thepreviously-mentioned calcium chemomechanical pump or by moreconventional ion transport channels known to those skilled in the art.CET involves such well-known therapies as defibrillation and pacing, andmay be sequenced either before or after the MPT and MPES phases. In somesuboptimal embodiments, explicit delivery of therapeutic agents may bemissing, for instance it may be the case that the therapeutic intent isonly to deliver Ca⁺ to the cytosol, in which case there may besufficient extracellular calcium present in ischemia for accomplishingthis goal utilizing MPES. Also, a patient may be resuscitated prior toCET, in which case there are only the MPT and MPES phases of therapy;there is thus a minimal configuration of the invention with includesonly the MPT phase consisting of only CPR and the MPES phase of therapy.

Referring to FIG. 6, one possible implementation has the function ofchest compression integrated with that of an externaldefibrillator/pacemaker such as manufactured by ZOLL Medical(Chelmsford, Mass.). The chest compression function may be provided bydevices such as a piston-based system such as that manufactured byMichigan Instruments (Michigan) or a constricting band system such asthat manufactured by Revivant Corp. (California). The integration maytake the form of physical integration of the defibrillator/pacemaker andthe chest compressor into a single device, but alternatively it may be afunctional integration of two separate devices by a communication meanssuch as a wireless scheme like Bluetooth or a serial communicationinterface such as RS232, USB or Ethernet.

When used by advanced cardiac life support personnel (ACLS), the MPTphase includes intravenous or intraosseus delivery of therapeutic agentsas well as an initial assessment of whether or not the cardiac arrestwas the result of asphyxia. In the case of asphyxial arrest as well ascardiac arrests with a presenting rhythm of asystole or PEA, the patientwill receive one minute of chest compressions combined with activeventilations while the therapeutic agents are being prepared in order toalleviate hypercarbia. A combination of norepinephrine (5 mg),epinephrine (1 mg), are then delivered as a bolus intravenously, with anIV infusion of a combination of 25% glucose, 50 IU soluble insulin perliter at an infusion rate of 1 mL·kg⁻¹·h⁻¹. The glucose/insulin solutionmay be included in the initial bolus. Norepinephrine enhances cyclic AMP(cAMP) which, in turn, results in increased glycogenolyis and glucoseuptake via the GLUT4 channels, and enhanced calcium uptake by the L-typecalcium channels resulting in enhanced contractility. Dobutamine may besubstituted for norepinephrine and epinephrine. The patient thenreceives one more minute of chest compressions.

In one implementation, the amino acid aspartate is delivered as part ofan initial intravenous infusion prior to the MPES phase. In anotherembodiment utilizing aspartate, the aspartate is delivered in an MPTinfusion phase, followed by electrical stimulation of the heartutilizing defibrillation or pacing therapy without any intervening MPESphase. The aspartate infusion is preferably a Ringer's solution with thesodium concentration adjusted to account for the additional sodium dueto the 20 mmol/L of sodium L-aspartate added to provide the L-aspartate.The infusate may also include the combination of glucose and insulin.Aspartate is particularly effective in increasing ATP production of themyocardium under the ischemic conditions of cardiac arrest by enhancinganaerobic ATP production in glycolysis. Aspartate also has thebeneficial effect of a reduction of fumarate in mitochondria thuspotentially lower the risk of reperfusion injury after a successfuldefibrillation. Normally, reduced nicotinamide adenine dinucleotide(NADH) generated from glycolysis is reoxidized to NAD+ by reduction ofpyruvate to lactate. Under ischemic conditions, this results in abuild-up of lactate in the cytosol which is harmful to the myocardium.This is avoided by aspartate or 2-oxoglutarate. Aspartate istransaminated to oxaloacetate with the resulting amino group transferredto form alanine by way of a reaction involving pyruvate and glutamate.Oxaloacetate is then converted to malate with an oxidation of NADH tocreate NAD+. Ischemia arrests glycolysis at the glyceraldehyde phosphatedehydrogenase step due to a lack of NAD+. Thus the increasedconcentrations of NAD+ due to the aspartate will result in significantlyenhanced ATP production without the deleterious lactate productionusually encountered in anaerobic glycolysis. The malate is thentransported across the mitochondrial barrier. During effective CPR orupon successful resuscitation of the patient when oxygenated blood isbeing delivered to the myocardium, the enhanced levels of malate leadsto enhancement of the reduction of fumarate to succinate, coupled withATP formation in complex 1 of the respiratory chain.

In cases where the presenting rhythm is VF, a defibrillation shock maybe delivered prior to the MPT and MPES phases as described in thepreceding paragraph. It has been found that substitution of vasopressinfor epinephrine in this situation provides better outcomes for thepatient.

Following the second one-minute cycle of chest compressions, thecatecholamines, ions and metabolites have been delivered via thecoronary arteries and their branches into the myocardium. In order toaccomplish delivery of the various therapeutic agents into the cytosol,one minute of MPES is delivered.

In one implementation, the MPES waveform delivered to the patient is amultiphasic waveform, e.g., as described in U.S. Pat. No. 6,096,063.Referring to FIG. 4 a, the waveform is composed of at least one biphasicpulse. The biphasic pulses are approximately 100-200 volts in amplitudeand may be concatenated, e.g., into a multiphasic pulse train up to 100ms in duration, though preferably a series of four 10 ms biphasic pulsefor a total of 40 ms. The biphasic pulses may additionally be shortenedin duration, thus increasing the frequency content of the MPES waveform.In another embodiment shown in FIG. 4 b, the individual biphasic pulsesare 500 microseconds in duration, with a 400 microsecond first phase and100 microsecond second phase with a spacing between pulses of 9.5 ms. Ithas been found that GLUT4 glucose transport channels respond to thesehigher frequencies while the longer duration, lower frequency 10-20 msduration biphasic pulses are more effective at stimulating themyocardial contraction that is necessary for the Ca⁺ chemomechanicalpump to function. The pulses are delivered at a rate of 0.1-4 Hz duringthe course of MPES treatment.

In an additional embodiment, pulses of different characteristics may beinterspersed to provide optimal transfer of the therapeutic agents. Forinstance, the pulse train of FIG. 4 a is alternated with that of FIG. 4b either singularly or in groups. The average amplitude of the pulsetrain can be adjusted by changing the duty cycle of the biphasic pulses.For instance, for shorter duration biphasic pulses, less thanapproximately 1 ms in duration, the myocardium responds to the averagecurrent of the pulse train. Thus, with a 50% duty cycle, there is verylittle effect on the myocardium. Increasing the duty cycle increases theaverage current. In some implementations, the capacitor voltage may becharge to an arbitrary value based on the measured impedance of thepatient prior to delivery of therapy as well as expected levels ofcurrent required for the therapy. During the delivery of the MPESpulses, the average current can be adjusted dynamically by altering thebiphasic pulse duty cycle. By adjusting the duty cycle, waveform shapeand rate of the pulses, the device can seamlessly adjust the type oftherapy delivered to the patient based on the measured underlyingcondition of the patient.

Referring to FIGS. 5,6 the electromagnetic (EM) energy delivery means 1is comprised of storage capacitor 2 which is charged to atherapeutically effective voltage by a charging circuit 4, under controlof the processing means 5, while relays 6, 7 and the H-Bridge 10 areopen.

Upon determination by processing means 5, using any existing methodsknown to those skilled in the art, of the appropriate time to deliverthe defibrillation energy to the patient, relay switches 14 and 15 areopened, and relay switches 6, 7 are closed. Then, the electronicswitches 16, 17, 18, and 19 of H-bridge 10 are closed to allow electriccurrent to pass through the patient's body in one direction, after whichelectronic switches 16, 17, 18, and 19 of H-bridge 10 are opened and 20,21, 22, and 23 of H-bridge 10 are closed to allow the electric currentto pass through the patient's body in the other direction. Relayswitches 14 and 15 are combined in double-pole double-throwconfiguration (DPDT) to reduce size and cost. Electronic switches 16-23are controlled by signals from respective opto-isolators, which are, inturn, controlled by signals from the processing means 5. As shown inFIG. 2, processing means 5 may be a microprocessor, such as a HitachiSH-3 40 combined with a read only memory device (ROM) 41, random accessmemory (RAM) 42, Clock 43, real time clock 44, analog-to-digital 45 anddigital-to-analog 46 converters, power supply 47, reset circuit 48,general purpose input/output 49, and user interface in the form of adisplay 49 and input keys 50 and other circuitry known to those skilledin the art. A measurement means 52 is provided for measurement ofelectrical, electrocardiographic, physiological or anatomical parametersof the patient, the processing means 5 controlling the waveformparameters of at least one of the discharge pathways based on thismeasurement. Relay switches 6, 7 which are also controlled by theprocessing means 5, isolate patient 3 from leakage currents of H-bridgeswitches 16-23 which may be about 500 microamperes.

Resistive circuit 55 that include series-connected resistors 57, 58, 59are provided in the current path, each of the resistors being connectedin parallel with shorting switch 66-68 controlled by processing means 5.The resistors may be of unequal value and stepped in a binary sequencesuch that with the various combinations of series resistance values,there are 2^(n) different combinations, where n is the number ofresistors. Immediately prior to delivering the therapeuticdefibrillation energy a smaller amplitude “sensing” pulse is deliveredby closing H-bridge switches 16-19 and the resistor shorting switches66-68 are all open so that current passes through the resistors inseries. The current sensing transformer 69 senses the current thatpasses through the patient through their respective electrode pairs 1 a,1 b, from which the processing means 5 determines the resistance of thepatient 3.

The initial sensing pulse is integral with, i.e., immediately followedby, a biphasic defibrillation waveform, and no re-charging of storagecapacitor occurs between the initial sensing pulse and the biphasicdefibrillation waveform. If the patient resistance sensed during theinitial sensing pulse is low, all of the resistor-shorting switches66-68 are left open at the end of the sensing pulse so that all of theresistors 57-59 remain in the current path (the resistors are thensuccessively shorted out during the positive phase of the biphasicdefibrillation waveform in the manner described below in order toapproximate a rectilinear positive phase). Thus, the current at thebeginning of the positive first phase of the biphasic defibrillationwaveform is the same as the current during sensing pulse. If the patientresistance sensed during the sensing pulse is high, some or all of theresistor-shorting switches 66-68 are closed at the end of the sensingpulse, thereby shorting out some or all of the resistors.

Thus, immediately after the sensing pulse, the biphasic defibrillationwaveform has an initial discharge current that is controlled bymicroprocessor 46, based on the patient impedance sensed bycurrent-sensing transformer 69. The current level of the sensing pulseis always at least 50 percent of the current level at the beginning ofpositive first phase, and the sensing pulse, like the defibrillationpulse, is of course a direct-current pulse.

By appropriately selecting the number of resistors that remain in thecurrent path, the processing means reduces (but does not eliminate) thedependence of peak discharge current on patient impedance, for a givenamount of charge stored by the charge storage device. During thepositive phase of the biphasic waveform, some or all of the resistors57-59 that remain in series with the patient 3 are successively shortedout. Every time one of the resistors is shorted out, an upward jump incurrent occurs in the waveform, thereby resulting in the sawtooth rippleshown in the waveform of FIG. 3. The ripple tends to be greatest at theend of the rectilinear phase because the time constant of decay (RC) isshorter at the end of the phase than at the beginning of the phase. Ofcourse, if all of the resistors have already been shorted outimmediately after the end of the sensing pulse, the positive phase ofthe biphasic waveform simply decays exponentially until the waveformswitches to the negative phase.

As is shown in FIG. 7, at the end of the positive phase, the currentwaveform decreases through a series of rapid steps from the end of thepositive phase to the beginning of negative phase, one of the stepsbeing at the zero crossing. Processing means 5 accomplishes this by (1)successively increasing the resistance of resistive circuit 55, 56 infixed increments through manipulation of resistor-shorting switches57-59, then (2) opening all of the switches in H-bridge 10 to bring thecurrent waveform down to the zero crossing, then (3) reversing thepolarity of the current waveform by closing the H-bridge switches thathad previously been open in the positive phase of the current waveform,and then (4) successively decreasing the resistance of resistancecircuit 55 in fixed increments through manipulation of resistor-shortingswitches 66-68 until the resistance of resistance circuit 55 is the sameas it at the end of the positive phase.

In one implementation a variable resistor 71 is provided in series withthe other resistors 57-59 to reduce the sawtooth ripple. Every time oneof the fixed-value resistors 57-59 is shorted out, the resistance ofvariable resistor 71 automatically jumps to a high value and thendecreases until the next fixed-value resistor is shorted out. Thistends, to some extent, to smooth out the height of the sawtooth ripplefrom about 3 amps to about 0.1 to 0.2 amps, and reduces the need forsmaller increments of the fixed-value (i.e., it reduces the need foradditional fixed-value resistor stages).

Unlike a defibrillation pulse which occurs, at most, at intervals of0.5-1 minute, the MPES pulses occur at approximately a 1 Hz rate.Charging circuit 4 charges the high voltage capacitor 2 to the requiredvoltage in the intervals between delivery of the MPES pulses.

The electromagnetic stimulation of the MPES waveform may take the formof magnetic stimulation via a electrical coil that receives the currentpulse from the high voltage capacitor 2. Magnetic stimulation canprovide some additional benefits over electrical stimulation in that thefields are unattenuated at the cytosolic level by the interveningconductive tissues such as blood and skeletal muscle.

Various agents for the enhancement of cardiac function may be deliveredin some implementations, including, for example, metabolites andmetabolic enhancing agents. The delivery may be performed in a varietyof ways, including, for example, intravenous, intraosseus, ortranscutaneous infusion. And delivery may include circulatoryenhancement to assist in delivery of the agent from the infusion site tothe coronary arteries. Circulatory enhancement can be performed in avariety of ways, including, for example, by manual chest compression, byusing an automatic chest compression device such as the Autopulse(available from Revivant, San Jose Calif.), or by using a cardiacmechanical pump.

Many other implementations of the invention other than those describedabove are within the invention, which is defined by the followingclaims. The invention applies to both defibrillation and cardioversion;in the claims, references to defibrillation should be interpreted asalso encompassing cardioversion. Some implementations of the inventiondo not require defibrillation or cardioversion. The invention applies,in general, to both internal and external defibrillation.

What is claimed is:
 1. Apparatus for treating a patient in cardiacarrest (e.g., in fibrillation, electrochemical dissociation, orasystole), the apparatus comprising: circuitry for generatingmicroperfusing pulses to the patient's cardiac tissue, wherein themicroperfusing pulses stimulating the cardiac tissue at an energy levelbelow a threshold sufficient to defibrillate the heart; and circuitryfor generating and pacing pulses and/or a defibrillation pulse to thepatient, wherein the microperfusing, pacing, and/or defibrillationpulses are generated by varying the duty cycle, shape, and/or rate ofdelivery of a series of pulses delivered from an energy storage device.2. The apparatus of claim 1 wherein the microperfusing, pacing, anddefibrillation pulses are generated by varying at least the duty cycleof a series of pulses delivered from the energy storage device.
 3. Theapparatus of claim 1 wherein the microperfusing, pacing, anddefibrillation pulses are generated by varying at least the shape of aseries of pulses delivered from the energy storage device.
 4. Theapparatus of claim 1 wherein the microperfusing, pacing, anddefibrillation pulses are generated by varying at least the rate ofdelivery of a series of pulses delivered from the energy storage device.5. Apparatus for treating a patient in cardiac arrest (e.g., infibrillation, electrochemical dissociation, or asystole), the apparatuscomprising: circuitry for generating a pacing pulse to the cardiactissue; and circuitry for generating a defibrillation pulse to thecardiac tissue, wherein the pacing pulse has substantially the samewaveform as the defibrillation pulse except for a difference inamplitude.